The recent reimbursement approval for proton therapy in the United States has created a boom in construction of proton therapy facilities. Proton therapy is distinguished from conventional (e.g., photon) radiotherapy by the ability to spare tissue beyond the proton beam's Bragg peak. For optimal dosing, the tight tolerances of the proton Bragg peak must be matched by exact localization of targets, while at the same assuring an increasing volume of patients undergoing such procedures. This increased volume of patients threatens to severely constrain the time available to accurately localize and immobilize targets in the patient. Conventional dosimetry approaches to proton therapy (i.e., that measure beam current) do not provide direct information about dose delivered to the tumor, and create a desire for methods of directly visualizing dose delivery in real time. Several investigators have proposed and implemented detection of in vivo activated positron- emitting compounds to monitor dose delivery in charged particle therapy (e.g., protons, carbon ions). A prototype dual-head on-line PET camera has been in place at a carbon therapy facility in Germany since 1998. This innovation has not been duplicated at other sites because of several technical issues, including low count statistics in the image, and difficulties in mounting the PET scanner so that it does not interfere with beam delivery. We propose to employ novel PET detector configurations that provide high count collection efficiency and additional flexibility for the technologist to aim the proton beam. We aim to introduce hardware and software improvements to on-line PET monitoring, in order to improve image quality and to implement a corrective strategy online for immediate feedback during a single administration, whether that administration is part of a fractionated series or is a single- shot (i.e., radiosurgery). PUBLIC HEALTH RELEVANCE: RELEVANCE The recent reimbursement approval for proton therapy in the United States has created a boom in construction of proton therapy facilities. Proton therapy is capable of tighter delivery of radiation therapy than other methods, creating a need for more accurate targeting and monitoring methods. We are building novel PET scanners that will reside in the proton therapy suite, and will which provide more rapid and accurate feedback to guide proton therapy.